Gulf War Illness (GWI) is a complex condition that involves persistent deregulation of multiple systems within the body including the immune, endocrine, and cardiovascular systems. The condition appears to affect both men and women who were deployed to the GW, with up to one-third of these affected Veterans remaining ill today. While treatment of both men and women has involved management of symptomatology, a lack of clear understanding of the underlying dysfunction associated with this condition remains. In an effort to understand the underlying mediators of dysfunction, our research group has developed a dynamic model to identify these mediators of persistence and relapse, with the primary goal of pinpointing the underlying mechanisms of the condition and targeting treatment more effectively. In this application we turn to gender differences. Utilizing this dynamic model that involves challenging a patient with exercise and drawing bloods at multiple times to map out mediators of genomic, cellular, and chemical response, we have studied 50 men and 10 women with GWI illness. While we have been able to analyze the data with enough power to know that the disease is mediated differently in men and women despite clinical similarities between the two genders, we have not been able to model the mediators of persistent illness in women to the point of identifying therapeutic targets as we have in men with GWI, entirely due to our small sample size. Our previous work in males with GWI has progressed to Phase 1 clinical trials, as supported by a newly awarded DoD consortium grant and a submitted VA clinical trials proposal. The aim of the consortium is to identify signaling mechanisms relevant to GWI in male patients and outline the most promising biomarkers tied to these signaling pathways and to target pathways for intervention studies that would not only improve symptomatology but ultimately reset homeostasis. In addition, we are also funded through the NIH to assess differences in genomic, cellular, and chemical response using a dynamic model among female patients with CFS/ME or fibromyalgia and healthy controls. With these studies underway, we are developing a more detailed understanding of the dysfunction associated with key metabolic pathways involved in GWI in men and in women with a related illness, CFS/ME. The clear missing link is the comparison of women with GWI to outline further differences in response between genders and develop effective tailored treatments for both men and women. In this merit application, we propose a value added study that incorporates our current research efforts to thoroughly explore sex differences across a platform that enables evaluation of genomic, cellular, and chemical response mediators in women with GWI using a sample size sufficient to support between-group comparisons and modeling of illness-modifying interventions. We also have an existing dynamic data set in women and men with chronic fatigue syndrome (CFS/ME), an interesting comparator group when comparing illness models. With existing data and the enhanced female GWI cohort we will be able to compare gender differences in terms of illness, illness mechanisms, and explore gender-specific therapeutic targets. By utilizing this information, we aim to understand the mediators of persistence and relapse in women with GWI and extend our research efforts to clinical trials based on dynamic modeling and therapeutic targets, as we have in men.